Chlormadinonacetat

Crystals from menthanol or ether

White to light-yellow...crystals

In double-distilled water, 0.16 mg/L

Very soluble in chloroform; soluble in acetonitrile; slightly soluble in ethanol and diethyl ether.

Specific optical rotation = +6 deg at 25 °C/D (c = 1 in CHCl3)

Optical rotation = -10.0 deg to -14.0 deg at 20 °C

197 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

199.43 Ų [M+H]+

Danger

H351 (70.8%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P260, P280, P318, P319, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 72 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H341: Suspected of causing genetic defects [Warning Germ cell mutagenicity]

Carc. 2 (70.8%)

Germ cell mutagenicity - Category 2

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing dust. Ensure adequate ventilation. Evacuate personnel to safe areas. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/

For more Disposal Methods (Complete) data for CHLORMADINONE ACETATE (9 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/

For more Preventive Measures (Complete) data for CHLORMADINONE ACETATE (20 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 7,000, determined from a structure estimation method(2), indicates that chlormadinone acetate is expected to be immobile in soil(SRC). Volatilization of chlormadinone acetate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.6X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Chlormadinone acetate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 7,000(SRC), determined from a structure estimation method(2), indicates that chlormadinone acetate is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.6X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 190(SRC), from an estimated log Kow of 3.95(6)and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Hydrolysis is not expected to be an important environmental fate process given estimated half-lives of 2.3 years and 84 days at pH values of 7 and 8, respectively(8). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), chlormadinone acetate, which has an estimated vapor pressure of 3.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2) is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase chlormadinone acetate may be removed from the air by wet or dry deposition(SRC). Chlormadinone acetate absorbs light at wavelengths of 283.5 and 286 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

For chlormadinone acetate, a concentration range of 0.04 to 0.15 ug/L was reported as a result of analysis of raw sewage entering 14 representative sewage plants within a 50-mile radius of Cincinnati, OH; the average concentration was 0.09 ug/L. The treated effluent concentration range was 0.03 to 0.14 ug/L, average 0.08 ug/L(1).

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of chlormadinone acetate can be estimated to be 7,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that chlormadinone acetate is expected to be immobile in soil.

/CASE REPORTS/ ... Drug-induced pure red cell aplasia (PRCA) is a rare secondary form of PRCA, and is usually acute and fully reversible by the withdrawal of the causative drugs. We report a rare case of PRCA in a prostate cancer patient treated with combined androgen blockade (CAB) consisted of leuprolide acetate as a luteinizing hormone-releasing hormone agonist and chlormadinone acetate as an antiandrogen. This case demonstrated that these drugs could be a cause of PRCA, and suggests that regular close monitoring for anemia is needed in prostate cancer patients treated with these drugs.

/GENOTOXICITY/ Cyproterone acetate (CPA), a synthetic progestin recently found to induce genotoxic effects in hepatocytes from female rats and from humans of both genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for their capacity to induce DNA repair synthesis as measured by quantitative autoradiography. Exposure of primary human hepatocytes for 20 hr to concentrations of CPA, CMA and MGA ranging from 2 to 50 uM induced positive responses in cultures from donors of both genders and the amounts of DNA repair elicited by the three progestins were similar. Under the same experimental conditions substantial differences were observed in the amounts of DNA repair elicited by the three progestins in primary hepatocytes from female rats, their potency decreasing in the following order CPA > CMA > MGA, and the three compounds failed to induce DNA repair in hepatocytes from male rats. ...

An estimated BCF of 190 was calculated in fish for chlormadinone acetate(SRC), using an estimated log Kow of 3.95(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for chlormadinone acetate is estimated as 5.6X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that chlormadinone acetate is expected to be essentially nonvolatile from water and moist soil surfaces(2). Chlormadinone acetate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-9 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Studies in male rats treated orally with chlormadinone acetate 50 mg/kg body weight/day for 21 days revealed atrophy of adrenal cortex, prostate, and pituitary corticotropin-producing cells. Female rats treated orally for 30 days with a dose ranging from 10 to 1000 mg/kg body weight/day developed significant decrease in uterine weights in the lowest dose group.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Male and female Beagle dogs were treated with chlormadinone acetate doses 0, 0.6 mg/kg body weight/day and 0.06 mg/kg body weight/day. Both sexes of dogs dosed with 0.6 mg/kg body weight/day chlormadinone acetate up to 7 months developed severe toxicological effects such as polydipsia, hyperglycemia, glomerulopathy and pyometra. The dose of 0.06 mg/kg/day for 5 months did not induce any toxicological symptoms. ... Apart from the hormonal effects on male and female reproductive organs, the major toxic effects might be due to development of diabetes mellitus.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a study of 22 mammary nodules which appeared in 14 dogs after 4 years of treatment with chlormadinone acetate (dose not specified), 12 were classified as nodular hyperplasia, 4 as benign, mixed tumors and 1 as an adenocarcinoma. By 7 years there had been an increase in the total number of neoplastic lesions of the mammary glands from 5 to 14 (benign, mixed tumors from 4 to 9; ductal papillomas from none to 3; and adenocarcinomas from 1 to 2). In the controls 1 benign, mixed tumor was observed.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Female Beagle dogs were fed chlormadinone acetate doses of 250 ug/kg body weight/day, commencing at 26 to 52 weeks of age. After 104 weeks, 6 out of 20 animals had small nodules (less than 1 cm) in mammary tissue, and similar but transitory nodules were noted in 4 untreated controls. Histological examination of the latter revealed no abnormal mammary proliferation. One further dog had a somewhat larger nodule, which at autopsy was found to be a benign tumor composed of connective tissue and some epithelial elements with proliferation of myoepithelial tissue.

For more Non-Human Toxicity Excerpts (Complete) data for CHLORMADINONE ACETATE (15 total), please visit the HSDB record page.

A base-catalyzed second-order hydrolysis rate constant of 9.5X10-2 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 2.3 years and 84 days at pH values of 7 and 8, respectively(1). Chlormadinone acetate absorbs light at wavelengths of 283.5 and 286 nm(2), and therefore may be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to chlormadinone acetate may occur through inhalation and dermal contact with this compound at workplaces where chlormadinone acetate is produced or used. Limited monitoring data indicate that the general population may be exposed to chlormadinone acetate via dermal contact with contaminated water. Exposure to chlormadinone acetate among the general population will also occur to those administered the drug, a progestogen. (SRC)

Chlormadinone acetate's production and use as a hormonal antineoplastic and veterinary estrus regulator may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.2X10-9 mm Hg at 25 °C indicates chlormadinone acetate will exist solely in the particulate phase in the atmosphere. Particulate-phase chlormadinone acetate will be removed from the atmosphere by wet or dry deposition. Chlormadinone acetate absorbs light at wavelengths of 283.5 and 286 nm, and therefore may be susceptible to direct photolysis by sunlight. If released to soil, chlormadinone acetate is expected to have no mobility based upon an estimated Koc of 7,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.6X10-10 atm-cu m/mole. Biodegradation data were not available. If released into water, chlormadinone acetate is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 170 suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism. Hydrolysis is not expected to be an important environmental fate process given estimated half-lives of 2.3 years and 84 days at pH values of 7 and 8, respectively. Occupational exposure to chlormadinone acetate may occur through inhalation and dermal contact with this compound at workplaces where chlormadinone acetate is produced or used. Limited monitoring data indicate that the general population may be exposed to chlormadinone acetate via dermal contact with contaminated water. Exposure to chlormadinone acetate among the general population will also occur to those administered the drug, a progestogen. (SRC)

Chlormadinone acetate (CMA) is a derivative of naturally secreted progesterone that shows high affinity and activity at the progesterone receptor. It has an anti-estrogenic effect and, in contrast to natural progesterone, shows moderate anti-androgenic properties. CMA acts by blocking androgen receptors in target organs and by reducing the activity of skin 5alpha-reductase. It suppresses gonadotropin secretion and thereby reduces ovarian and adrenal androgen production. CMA shows high contraceptive efficacy by inhibiting ovulation due to its ability to suppress or disrupt endogenous gonadotropin secretion and, by this, inhibits follicular growth and maturation. In addition, it suppresses endometrial thickness and increases the viscosity of cervical mucus. ...

The ovulation response to electrical stimulation of the median eminence, or to the intrapituitary infusion of median eminence extract, was observed in control rabbits and animals pre-treated with chlormadinone acetate. Chlormadinone acetate pre-treatment did not significantly reduce the proportion of rabbits ovulating in response to electrical stimulation. However, there was a significant reduction in the average number of ruptured follicles when compared with the animals in the control group. Chlormadinone acetate pre-treatment significantly reduced the proportion of animals ovulating in response to the intrapituitary infusion of median eminence extract as compared with the control series. However, there was no significant reduction in the average number of ruptured follicles (in those rabbits that ovulated) when compared with the control groups. Chlormadinone acetate pre-treatment produced no significant effect upon either the proportion of animals ovulating, or the average number of ruptured follicles, following i.v. injection of 50 ug LH.5. The conclusion drawn is that chlormadinone acetate blocks copulattion-induced ovulation in the rabbit by action at a site in the central nervous system located above the median eminence. The possible effects of chlormadinone acetate upon the secretion of FSH, the pituitary sensitivity to releasing factors and the ovarian sensitivity to LH are discussed.

Studies with the human breast cancer cell line ZR-75-1, which contains functional estrogen, progesterone and androgen receptors, suggest that chlormadinone acetate inhibited the growth of these cells by an interaction of androgen and progesterone receptor-mediated mechanisms.

Groups of 8-12 male Sprague-Dawley Crl:CD(SD)Br rats were castrated and injected immediately thereafter twice daily for 14 days with one of a number of synthetic progestogens, including chlormadinone acetate, used in the treatment of prostate cancer. Controls received the vehicle, 1% gelatine in 0.9% saline... Dihydrotestosterone was injected at a dose of 150 ug twice daily for 14 days as a positive control. All animals were killed on the morning after the last day of treatment, and the ventral prostate and adrenals were removed and weighted; furthermore, the prostatic content of ornithine decarboxylase was measured, as it is consider to be a highly specific, sensitive of androgenic activity in the prostate. Dihydrotestosterone increased the ventral prostate weight to 43% above that of castrated controls. Chlormadinone acetate was less potent than dihydrotestosterone but caused significant increases in prostate weight, by about 22% at 3 mg and 36% at 10 mg per injection. Whereas dihydrotestosterone caused a 14-fold increase in ornithine decarboxylase activity in the prostate, chlormadinone acetate caused a 5.3-fold increase at 3 mg and an 11.8-fold increase at 10 mg. Chlormadinone acetate thus has weak but significant androgenic activity in the rat ventral prostate.

... After a single dose of CMA the half-life time is around 34 hours and after multiple dose administration approximately 38 hours. ...

Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. ... Mean t(1/2,z) of CMA was approximately 25 hr after single dosing and 36-39 hr at steady state. ... The t(1/2,z) of CMA was 36-39 hr after multiple dosing, which is considerably shorter than the 80 hr often quoted in the literature.

The half-life and metabolic clearance rate of chlormadinone acetate were computed after a single iv injection of 60 to 90 mcCi 1-alpha-tritiated-chlormadinone acetate (specific activity 222 mcCi/mg) into 7 women aged 34-52 years. Plasma was extracted with acetone:MeOH for total radioactivity; then extracted with water and ether for free steroid radioactivity; then with n-butanol for conjugated steroid radioactivity; and finally extracted with chloroform:MeOH and chromatographed on thin layer with ether:benzene for specific radioactivity due to chlormadinone acetate. Blood samples were taken at .25, .5, 1, 8, 24 hours and every 24 hours for 5 days. The mean half-life of radioactivity specifically indentified as chlormadinone acetate for the first 24 hours was 2.6 hours, and after 24 hours was 81.8 hours, calculated by TAIT and BURSTEIN's method. ...

After intravenous injection of radiolabelled chlormadinone acetate, the steroid and its metabolites have an initial rapid half-life of 2.4 hours, followed by a slow half-life of 80.1 hours.

The major metabolites of chlormadinone acetate are 2alpha- hydroxychlormadinone acetate and 3beta-hydroxychlormadinone acetate. Incubation of chlormadinone acetate with human or rat liver microsomes produces mainly the 3beta-hydroxy metabolite. In contrast, incubation with microsomes from phenobarbital-treated rats produces the 2alpha-hydroxy metabolite, indicating that the metabolite pattern is dependent on the hepatic monoxygenase state.

Compounds which inhibit or antagonize the biosynthesis or actions of androgens.

Oral contraceptives which owe their effectiveness to hormonal preparations.

Oral contraceptives which owe their effectiveness to synthetic preparations.

... Pharmacokinetic studies have shown rapid and almost complete absorption after oral administration, and chlormadinone acetate is being bound to albumin rather than SHBG (Sex-Hormone-Binding-Globulin). Multiple dosing studies have demonstrated that steady state is reached by day 7 after oral administration with peak plasma concentrations in the region of 2 ng/mL. ...

The half-life and metabolic clearance rate of chlormadinone acetate were computed after a single iv injection of 60 to 90 mcCi 1-alpha-tritiated-chlormadinone acetate (specific activity 222 mcCi/mg) into 7 women aged 34-52 years. Plasma was extracted with acetone:MeOH for total radioactivity; then extracted with water and ether for free steroid radioactivity; then with n-butanol for conjugated steroid radioactivity; and finally extracted with chloroform:MeOH and chromatographed on thin layer with ether:benzene for specific radioactivity due to chlormadinone acetate. Blood samples were taken at 0 .25, 0.5, 1, 8, 24 hours and every 24 hours for 5 days. ... All 4 curves, total radioactivity, conjugated steroids, free steroids, and specific activity had the same biphasic form: a rapid loss for about 24 hours, and an approaching equilibrium after 24 hours. The metabolic clearance rate was 42.61 liters per day... These data generate an estimate of the concentration of chlormadinone acetate in plasma of women taking 0.5 mg daily: about .45 ng/mL, i.e. about one-thirteenth the concentration of progesterone.

Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 hr after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 hr after single dosing and 36-39 hr at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 hr after multiple dosing, which is considerably shorter than the 80 hr often quoted in the literature.

The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol and chlormadinone acetate (Bellissima as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 hr post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/mL (test) and 129.12 pg/mL (reference). In the case of chlormadinone acetate, Cmax averaged 6.9566 ng/mL (test) and 6.6663 ng/mL (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/mL x hr (test) and 1380.49 pg/mL x hr (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/mL x hr (test) and 58.111 ng/mL x hr (reference). The median of tmax of ethinylestradiol was 1.5 hr for both test and reference and the median of tmax of chlormadinone acetate 1.0 hr (test) and 1.5 hr (reference). Plasma elimination half-lives (t1/2) of ethinylestradiol were 14.96 hr (test) and 15.41 hr (reference) and of chlormadinone acetate 56.63 hr (test) and 56.17 hr (reference), respectively. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for Cmax of ethinylestradiol, as the point estimator and the 90% confidence interval for the Cmax ratio are 96.18% (90.82%-101.86%). Regarding the AUC(0-infinity) ratio of chlormadinone acetate, the point estimator is 91.60% and the 90% confidence interval 84.08%-99.79%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90% confidence of Cmax of this active agent (104.72% [95.76%-114.53%]). Bioequivalence between test and reference formulation was demonstrated since for both ethinylestradiol and chlormadinone acetate all 90% confidence intervals of AUC(0-infinity) and Cmax fall into the generally accepted range of 80%-125%.

After intravenous injection of radiolabelled chlormadinone acetate, the steroid and its metabolites have an initial rapid half-life of 2.4 hours, followed by a slow half-life of 80.1 hours. The mean metabolic clearance rate is 126 L/day for chlormadinone acetate and 42.6 L/day for chlormadinone acetate and its metabolites. The long half-life and slow elimination rate are probably due to accumulation of the drug in fat tissue.

MEDICATION

MEDICATION (VET)

... By the treatment of 17alpha-acetoxyprogesterone with ethyl orthoformate in the presence of an acid catalyst to produce the 3-enol ether of the corresponding 3,5-dione; conversion of this enol ether to 6-chloro-17alpha-acetoxyprogesterone with N-chlorosuccinimide is followed by dehydrogenation with chloranil.

Mixture wth ethinyl estradiol

Mixture with mestranol

Chlormadinone acetate is available commercially as tablets, either alone or in combination with ethinylestradiol or mestranol.

Estrogen-free antifertility agent ... available in England .. less effective but with less tendency to cause blood clotting than estrogenic types

...manufactured or formulated in Argentina, Austria, France, Germany, Japan, Mexico, and Switzerland.